Decreases in brain corticotropin-releasing hormone (CRH) may contribute to pathological feeding behavior and metabolic rate seen in obesity and related metabolic disorders. Neurocrine has identified a novel protein in postmortem human brain which binds and inactivates CRH with high affinity (CRH-binding protein; CRH-BP) within brain areas that are implicated in the regulation of energy balance. Peptide ligands that dissociate CRH from the CRH-BP replenish brain levels of "free CRF" and exert significant sympathomimetic properties in animal models of obesity. Neurocrine Biosciences in parallel studies is optimizing non-peptide CRH- BP antagonists for both in vitro potency as well as in vivo efficacy in rodents following systemic administration. The present proposal is devoted to identifying and characterizing the extent to which the preclinical and clinical models of metabolic disorders are susceptible to modification via manipulation of brain CRH and pituitary-adrenal stress axes. Two data sets with implications for eventual medications development will be generated: l) the preclinical validation of CRH receptor agonists and CRH-binding protein ligand inhibitors in animal models which provide predictive validity for human models of obesity and 2) the clinical identification and refinement of physiological parameters which define the role of stress and hypothalamo-pituitary-adrenal activation in a constellation of human metabolic disorders.